Seven transmembrane-spanning receptors (7TMRs or G protein-coupled receptors, GPCRs) represent the largest family of signal-transducing molecules known. 7TMRs convey signals for light and many extracellular regulatory molecules, such as, hormones, growth factors and neurotransmitters, that regulate every cell in the body. Dysregulation of 7TMRs has been found in a growing number of human diseases and 7TMRs have been estimated to be the targets of more than 30% of the drugs used in clinical medicine today. Thus, discovery of probes/drugs for 7TMRs is an important goal of biomedical research. We have begun our research using high throughput screening (HTS) for low molecular weight (LMW) ligands for 7TMRs with the receptor for thyroid-stimulating hormone (TSH-R). During this year, we employed a cell-based assay that we developed for activation of TSH-R by LMW agonists and a complementary assay for LMW inhibitors of TSH stimulation of TSH-R for HTS. We identified new agonists for TSH-R that show excellent selectivity because they do not activate the closely related receptors for luteinizing hormone or follicle-stimulating hormone. These are the first LMW agonists for TSH-R reported. We continue to modify these compounds chemically to improve their selectivities, affinities and efficacies. We also identified the first LMW antagonist for TSH-R. Of particular note, is our observation that this antagonist not only inhibits stimulation of TSH-R by TSH but also by thyroid-stimulating antibodies (TsAbs) from patients with Gravess hyperthyroidism.